Transplantation systems such as organ transplantations have become important, effective and at times the sole therapies for many life-threatening end-stage diseases.
However, injurious immune responses are still the major barrier for successful transplantation. This is manifested in irreversible and life-threatening graft failure (host-versus-graft response, or HVG) or pathological immune reactivity of bone-marrow transplants graft-versus-host disease (GVHD). Importantly, current immunosuppression holds severe side-effect that limit the possibility of dose increment.
Pancreatic islet transplantation can provide type-1 diabetes patients with functional islets and physiological circulating glucose levels. However, shortage of human donors represents a critical obstacle. Islet xenograft transplantation from non-human donors provides an alternative for human islet allotransplantation; in addition to providing an array of islet sources, xenografts offer the advantage of elective procedures (that is, the donor is recruited upon availability rather than the patient), and potentially manipulating donor cells towards superior islet function. However, the xenoimmune response is exceptionally rigorous, and the side effects encountered with use of current immunosuppression outweighs the benefit of the procedure.
The immunological mechanism of xenograft rejection is distinct to allograft. Xenograft rejection is largely attributed to vast antigen disparity between species, thus triggering multiple arms of the immune response. Indeed, in addition to host CD4+ T cell involvement, evidence suggests that CD8+ T cells and B cells partake in xenograft rejection. Additionally, inflammation limits islet xenograft survival, particularly in early days post-transplantation, a challenging therapeutic obstacle considering that diabetogenic corticosteroids are excluded from current islet transplantation protocols. Within this context, the desired emergence of protective regulatory T cells (Tregs) appears further intangible.
Experimentally, xenograft survival prolongation has been achieved by several routes, most of which may not easily translate to human use. Of these, approaches that deplete immune cells have been experimentally successful and have entered human use. Anti-thymocyte-globulin (ATG), a regimen comprised of polyclonal antibodies that temporarily deplete T cells, is currently used for prevention of acute rejection in organ transplantation. Combination of anti-CD4 and anti-CD8 antibodies in mice (referred to as T cell debulking therapy) may represent the use of ATG in patients, as it achieves a similar temporary decline in T-cell numbers (Tchorsh-Yutsis et al. Transplantation 2011; 91(4):398-405; Tchorsh-Yutsis et al. Diabetes 2009; 58(7):1585-1594). Temporal T cell depletion delays clonal T cell activation in the associated draining lymph nodes (DLN) and allows grafted islets to evade T cell-mediated destruction in the first ˜2 weeks post-transplantation. Indeed, anti-CD8 and anti-CD4 antibodies extend islet xenograft survival, albeit not indefinitely (Koulmanda et al. Xenotransplantation 2004; 11(6):525-530).
Human α1-antitrypsin (hAAT), a readily available plasma-derived protein with potent anti-inflammatory and tissue-protective activities, promotes islet all ograft survival and induces strain-specific immune tolerance in the absence of a direct effect on T-cell responses (Shahaf et al., Mol Med. 2011 September-October; 17(9-10): 1000-1011; Lewis et al., Proc Natl Acad Sci USA 2008; 105(42):16236-16241; and Lewis et al., Proc Natl Acad Sci USA 2005; 102(34):12153-12158). hAAT also targets anti-islet autoimmune responses in animals (Koulmanda et al., Proc Natl Acad Sci USA 2008; 105(42):16242-16247). The cellular targets of hAAT include non-T cells such as dendritic cells, B lymphocytes, macrophages and neutrophils, resulting in reduced levels and activity of inflammatory mediators such as IL-1β, tumor necrosis factor (TNF) α, monocyte chemotactic protein (MCP)-1 and nitric oxide, as well as elevating levels of IL-10 and IL-1 receptor antagonist. hAAT has been shown to directly protect islets from inflammatory injury, apoptosis and isolation-related damage.
US Pat. Appl. No. 20090118162, to an inventor of the current invention and co-workers, relates to compositions and methods for inhibition of graft rejection and promotion of graft survival.
US Pat. Appl. No. 20090220518, to an inventor of the current invention and co-workers, relates to treating, reducing or preventing transplantation rejection and/or side effects associated with transplantation.
Nowhere in the background art is it taught or suggested that xenograft rejection may be prevented by combination therapy comprising AAT and temporary T cell depletion, particularly, anti-CD4 and anti-CD8 antibodies administration.
There remains an unmet medical need for providing methods for preventing and treating xenograft rejection, and for attenuating host responses in transplantation of tissues, organs or cells.